The pathogenesis of coronary arterial spasm and its role in ischemic heart disease has long been a subject of great interest to both clinicians and basic scientists. Although extensive research efforts have been made to elucidate the mechanism of coronary vasospasm, it has, to a large extent, remained not well understood. In our studies with isolated canine as well as human coronary arteries, we reported that an important bioregulatory enzyme, thrombin, which is readily activated during vascular injury produced two contrasting coronary vascular effects. In coronary arteries with intact endothelium, thrombin produces a potent vasorelaxation, while in endothelium-disrupted canine and human coronaries or in ischemically injured canine coronary arteries, thrombin produces a potent vasoconstrictory effect. Results of these studies suggest that intimal endothelial cells might play a far more important role in the regulation of coronary circulation and vascular reactivity than has been thought previously, and that an altered vascular response in coronary arteries with pathologically or mechanically injured endothelium may contribute to the development of severe coronary vasoconstriction and vasospasm. Therefore, the primary overall objective as well as the long term goal of our research proposal is to study the pathophysiological role of intimal endothelial cells in the modulation of human coronary vascular reactivity and its alterations in ischemic heart disease. Specifically, attempts will be made 1) to determine the mechanism(s) as well as the pathophysiological role of thrombin- induced endothelium-dependent vasodilation and, perhaps more importantly, its direct endothelium-independent vasoconstriction in human coronary arteries, 2) to determine the effects of myocardial ischemia and atherosclerosis on human coronary vascular responsiveness to thrombin and other vasoactive agents, and 3) to determine possible changes in the vascular responsiveness of human saphenous veins to thrombin and other vasoactive agents following their transplantation to the coronary circulation. It is hoped that results of these proposed studies will provide a better control of the patency of the grafts and human coronary arteries to minimize the incidences of recurring occlusion.